This project will study the cell-mediated rejection of xenogeneic tissues. According to the investigators, preliminary studies have shown that rejection of discordant xenogeneic skin grafts by mice is mediated primarily by CD4+ T cells, that direct murine T cell responses to xenoantigens in vitro are extremely weak, but that nonetheless, mice still reject xenogeneic skin grafts in vivo more vigorously than they do allografts. These findings suggest that the investigators' current in vitro assays measure the wrong T cell response, that the mechanisms of T cell-mediated xenograft rejection may differ from those of allografts, and that either different forms of immunosuppression or selective genetic modifications of xenogeneic donors will be needed to inhibit T cells-mediated rejection of xenogeneic heart transplants. According to the investigators, the primary issue addressed in these studies is whether the greater strength of cell-mediated xenogeneic immunity resides in the indirect pathway (Specific Aim #1), by which peptides of foreign antigens are presented by recipient MHC molecules, or in the direct pathway (Specific Aim #2) by which xenogeneic antigens are recognized on the donor's antigen presenting cells. The proposed experiments make use of several new genetically-altered mouse strains which enable the investigators to investigate these mechanisms of graft rejection separately. To extend the results of the investigators mouse studies to more clinically relevant species combination, they will perform experiments in Specific Aim #3 which examine the T cell responses of primates to pig antigens. In addition to in vitro assays, the investigators will adoptively transfer primate lymphocytes to RAG-1 knock out mice to study direct versus indirect rejection of xenografts in vivo. Finally, the investigators will study the T cell-mediated resistance to xenogeneic bone marrow engraftment in Specific Aim #4. The investigators will use genetically- altered mouse strains to determine whether director or indirect T cell responses are primarily responsible for rejection of xenogeneic bone marrow. The fundamental purpose of these experiments, according to the investigators, is to determine whether efforts to modify cellular immunity to achieve clinical xenogeneic heart transplantation should focus primarily on altering the recipient s responses (the indirect pathway) or on genetic modifications of the donor animals (the direct pathway).